Mouse liver compensates loss of Sgpl1 by secretion of sphingolipids into blood and bile

  • Sphingosine 1 phosphate (S1P) lyase (Sgpl1) catalyses the irreversible cleavage of S1P and thereby the last step of sphingolipid degradation. Loss of Sgpl1 in humans and mice leads to accumulation of sphingolipids and multiple organ injuries. Here, we addressed the role of hepatocyte Sgpl1 for regulation of sphingolipid homoeostasis by generating mice with hepatocyte-specific deletion of Sgpl1 (Sgpl1HepKO mice). Sgpl1HepKO mice had normal body weight, liver weight, liver structure and liver enzymes both at the age of 8 weeks and 8 months. S1P, sphingosine and ceramides, but not glucosylceramides or sphingomyelin, were elevated by ~1.5–2-fold in liver, and this phenotype did not progress with age. Several ceramides were elevated in plasma, while plasma S1P was normal. Interestingly, S1P and glucosylceramides, but not ceramides, were elevated in bile of Sgpl1HepKO mice. Furthermore, liver cholesterol was elevated, while LDL cholesterol decreased in 8-month-old mice. In agreement, the LDL receptor was upregulated, suggesting enhanced uptake of LDL cholesterol. Expression of peroxisome proliferator-activated receptor-γ, liver X receptor and fatty acid synthase was unaltered. These data show that mouse hepatocytes largely compensate the loss of Sgpl1 by secretion of accumulating sphingolipids in a specific manner into blood and bile, so that they can be excreted or degraded elsewhere.

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Author:Anna Katharina SpohnerGND, Katja Jakobi, Sandra TrautmannGND, Dominique Jeanette ThomasORCiDGND, Fabian Schumacher, Burkhard Kleuser, Dieter LütjohannORCiD, Khadija El-Hindi, Sabine GröschORCiDGND, Josef PfeilschifterGND, Julie D. Saba, Dagmar Meyer zu HeringdorfORCiDGND
Parent Title (English):International journal of molecular sciences
Publisher:Molecular Diversity Preservation International
Place of publication:Basel
Document Type:Article
Date of Publication (online):2021/09/30
Date of first Publication:2021/09/30
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2021/12/21
Tag:SGPL1; bile; ceramides; cholesterol; liver; sphingosine-1-phosphate
Page Number:22
First Page:1
Last Page:22
This work was supported by the Deutsche Forschungsgemeinschaft SFB 1039 to A.K.S., K.J., S.T., D.T., K.E.-H., S.G., J.P., D.M.z.H. and Public Health Service grant NIH R01 DK115669 to J.D.S. The article processing charges were provided by the Open Access Publication Fund of the Goethe University Frankfurt.
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Licence (German):License LogoCreative Commons - Namensnennung 4.0